Acetylation- and ubiquitination-regulated SFMBT2 acts as a tumor suppressor in clear cell renal cell carcinoma.

IF 5.7 2区生物学 Q1 BIOLOGY

Biology Direct Pub Date : 2024-05-11 DOI:10.1186/s13062-024-00480-3

Qingpeng Xie, Bin Hu, Haosong Li

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引用次数: 0

Abstract

Background: Clear cell renal cell carcinoma (RCC) is the most common kidney tumor. The analysis from medical database showed that Scm-like with four MBT domains protein 2 (SFMBT2) was decreased in advanced clear cell RCC cases, and its downregulation was associated with the poor prognosis. This study aims to investigate the role of SFMBT2 in clear cell RCC.

Methods: The expression of SFMBT2 in clear cell RCC specimens were determined by immunohistochemistry staining and western blot. The overexpression and knockdown of SFMBT2 was realized by infection of lentivirus loaded with SFMBT2 coding sequence or silencing fragment in 786-O and 769-P cells, and its effects on proliferation and metastasis were assessed by MTT, colony formation, flow cytometry, wound healing, transwell assay, xenograft and metastasis experiments in nude mice. The interaction of SFMBT2 with histone deacetylase 3 (HDAC3) and seven in absentia homolog 1 (SIAH1) was confirmed by co-immunoprecipitation.

Results: In our study, SFMBT2 exhibited lower expression in clear cell RCC specimens with advanced stages than those with early stages. Overexpression of SFMBT2 inhibited the growth and metastasis of clear cell RCC cells, 786-O and 769-P, in vitro and in vivo, and its silencing displayed opposites effects. HDAC3 led to deacetylation of SFMBT2, and the HDAC3 inhibitor-induced acetylation prevented SFMBT2 from SIAH1-mediated ubiquitination modification and proteasome degradation. K687 in SFMBT2 protein molecule may be the key site for acetylation and ubiquitination.

Conclusions: SFMBT2 exerted an anti-tumor role in clear cell RCC cells, and HDAC3-mediated deacetylation promoted SIAH1-controlled ubiquitination of SFMBT2. SFMBT2 may be considered as a novel clinical diagnostic marker and/or therapeutic target of clear cell RCC, and crosstalk between its post-translational modifications may provide novel insights for agent development.

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乙酰化和泛素化调控的 SFMBT2 是透明细胞肾细胞癌的肿瘤抑制因子。

背景：透明细胞肾细胞癌（RCC透明细胞肾细胞癌（RCC）是最常见的肾脏肿瘤。医学数据库的分析表明，具有四个 MBT 结构域的 Scm 样蛋白 2（SFMBT2）在晚期透明细胞 RCC 病例中的含量降低，其下调与不良预后相关。本研究旨在探讨SFMBT2在透明细胞RCC中的作用：方法：采用免疫组化染色和免疫印迹法检测SFMBT2在透明细胞RCC标本中的表达。通过MTT、菌落形成、流式细胞术、伤口愈合、Transwell实验、裸鼠异种移植和转移实验评估了SFMBT2对透明细胞RCC增殖和转移的影响。共免疫沉淀法证实了SFMBT2与组蛋白去乙酰化酶3（HDAC3）和seven in absentia homolog 1（SIAH1）的相互作用：结果：在我们的研究中，SFMBT2在晚期透明细胞RCC标本中的表达量低于早期RCC标本。过表达 SFMBT2 可抑制透明细胞 RCC 细胞（786-O 和 769-P）在体外和体内的生长和转移，而沉默 SFMBT2 则显示出相反的效果。HDAC3导致SFMBT2去乙酰化，HDAC3抑制剂诱导的乙酰化阻止了SFMBT2被SIAH1介导的泛素化修饰和蛋白酶体降解。SFMBT2蛋白分子中的K687可能是乙酰化和泛素化的关键位点：SFMBT2在透明细胞RCC细胞中发挥抗肿瘤作用，HDAC3介导的去乙酰化促进了SIAH1控制的SFMBT2泛素化。SFMBT2可被视为透明细胞RCC的新型临床诊断标志物和/或治疗靶点，其翻译后修饰之间的相互影响可为药物开发提供新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biology Direct 生物-生物学

CiteScore

6.40

自引率

10.90%

发文量

审稿时长

7 months

期刊介绍： Biology Direct serves the life science research community as an open access, peer-reviewed online journal, providing authors and readers with an alternative to the traditional model of peer review. Biology Direct considers original research articles, hypotheses, comments, discovery notes and reviews in subject areas currently identified as those most conducive to the open review approach, primarily those with a significant non-experimental component.